Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exerts pleiotropic effects on whole- body energy homeostasis. When administered pharmacologically to obese, diabetic rodents and non-human primates, FGF21 elicits robust anti-hyperglycemic, anti-hyperlipidemic, and anti-obesity effects, thus making it an attractive new drug for the treatment of obesity and metabolic diseases in humans. The weight-lowering effects of FGF21 have been attributed in part to its ability to augment thermogenesis and energy expenditure; however, the tissue targets of FGF21 required for its anti-obesity effects and the mediator(s) thereof are currently unknown. Preliminary data in this application indicate that FGF21 signaling in adipose tissue is required for its weight-lowering effects in obese mice. In addition, we found that bone morphogenetic protein 8b (Bmp8b) is the most highly induced gene in brown adipose tissue (BAT) in response to FGF21 treatment in both lean and obese mice - an effect that was lost in the absence of FGF21 signaling in adipose tissue. These data are particularly intriguing in light of recent findings that Bmp8b is a novel regulator of BAT thermogenesis and energy balance. In fact, activation of BAT has been proposed as a new strategy for the treatment of human obesity. Thus, we hypothesize that Bmp8b is a key mediator of the anti-obesity effects of FGF21. The current proposal aims to determine whether Bmp8b is required for FGF21 to increase thermogenesis, energy expenditure and body weight loss in diet-induced obese mice, and to stimulate transcriptional changes in brown and white adipose tissue (WAT). Furthermore, complementary in vitro and in vivo experiments are proposed to investigate how FGF21 regulates the activity of the Bmp8b promoter in BAT. This will be accomplished by combining in vitro studies of brown adipocytes in primary culture with in vivo studies using genetically-modified mouse models in which Bmp8b is deleted. Collectively, these studies will provide insight into the novel relationship between FGF21 and Bmp8b in BAT, and shed light on FGF21's pharmacologic basis of action as it pertains to modulation of energy balance in vivo.!